Breast cancer is the most frequently diagnosed life-threatening cancer in women. As a result, there is a critical need for the development of a safe and effective drug therapy for its treatment. Curcumin, a secondary metabolite isolated from Curcuma longa, has been shown to exhibit an impressively broad range of pharmacological effects. Despite its powerful interaction with a diverse set of cellular targets, Curcumin has several drawbacks that limit its potential as a therapeutic agent. One of the most common approaches to overcoming these limitations is the design and synthesis of novel Curcumin analogs. This study was conducted in support of the ongoing search for new molecules that are effective enough for the treatment of Triple-negative breast cancer while causing only minor side effects. Hence, several symmetrical monocarbonyl analogs of Curcumin with cyclopentanone, cyclohexanone and 4-piperidone as central core, were synthesized by Claisen-Schmidt condensation reaction. Their structures were identified by measuring the melting points, as well as using FTIR and UV/VIS spectroscopic techniques. To assess the cytotoxic activities of the analogs against MDA-MB-231 Breast Cancer Cells and to identify the significant structural features responsible for these molecules' potency, combined 2D- and 3D-Quantitative structure-activity relationship (QSAR) models were developed. The generated QSAR models demonstrated acceptable internal validation, as well as good external predictive capacity, indicating that they can be used to design similar compounds. These results suggest that the synthesized candidate drugs have promising cytotoxic potential against MDA-MB-231 cancer cells and should be further investigated both in vitro and in vivo.